PROJECT SUMMARY Significance and Background: Children with Down syndrome (DS), irrespective of having other risk factors, are at increased risk for respiratory syncytial virus (RSV) infection. Worldwide RSV is the most common cause of lower respiratory tract infections (LRTI) in infants and young children. Early life RSV LRTI further adversely influences the developing lung and immune system, and sets up children with DS for an increased risk of other long term respiratory diseases. Children with DS may therefore potentially benefit from RSV immunoprophylaxis, the only currently available pharmacological strategy to prevent RSV LRTI. However, insufficient data limit routine use of RSV immunoprophylaxis in children with DS to the same qualifying conditions as children without DS (premature birth < 29 weeks, chronic lung disease, or hemodynamically significant congenital heart disease) per American Academy of Pediatrics guideline. Objectives, Hypothesis and Specific Aims: Our overarching hypotheses are: 1) In children with DS RSV LRTI early in life increases the risk of respiratory morbidity through age 6 years, 2) Administration of RSV immunoprophylaxis reduces RSV LRTI morbidity and later respiratory morbidity caused by RSV LRTI early in life, and 3) Administration of RSV immunoprophylaxis offsets the costs of both RSV LRTI related hospitalization during the first 2 years of life and respiratory morbidity through age 6 years. To test the hypotheses, we will: 1) Determine and quantify the prevalence of severe RSV LRTI in the first 2 years of life and the association of RSV LRTI with respiratory morbidity through age 6 years; 2) Characterize the receipt of, safety of, and adherence to RSV immunoprophylaxis; 3) Determine the short-term effectiveness of RSV immunoprophylaxis on reducing RSV LRTI healthcare visits and the long-term effectiveness on childhood respiratory outcomes, 4) Determine the cost-effectiveness of RSV immunoprophylaxis administration in reducing RSV LRTI and later respiratory morbidity in children with DS. Research Design: We will conduct a large population-based birth cohort study of 4,063 children with DS born 1996-2018 and enrolled in the Tennessee Medicaid Program or the Department of Defense military healthcare system, the largest cohort ever conducted in this population. Impact: The knowledge gaps about the burden of RSV infection and the effectiveness of RSV immunoprophylaxis in children with DS leave policy makers, clinicians and patients unable to make informed clinical decisions. The proposed research, the largest study ever conducted, is in direct response to the American Academy of Pediatrics call for adequately powered studies to answer the question and inform policy on effectiveness of RSV immunoprophylaxis in this high risk population. Results from this study will provide information in informing clinical care and policy, and more importantly may improve human health in children with DS with a readily available and safe therapy.